Project Summary Ischemic injury in the myocardium causes several maladaptive structural and function changes during the repair and remodeling phases. Decreased mitochondrial function and increased collagen deposition are two major characteristics of post-ischemic injury, and both play major roles in tissue repair, cell death/survival and preservation of long-term cardiac function. The cardiac remodeling field has traditionally focused on the structural types I and III collagen and their importance in scar formation and aberrant fibrosis. We have evidence that the non-fibrillar type VI collagen (Col6) plays a critical, yet unappreciated, role in post-MI remodeling. Col6 orchestrates fibril formation and organization, and anchors type I collagen to the basement membrane in several tissues. Mutations in Col6 cause a well-described but rare skeletal muscle myopathy known as Bethlam Myopathy, a disease characterized by progressive skeletal muscle weakness due to early opening of the mitochondrial permeability transition pore (mPTP) and premature myocyte apoptosis. Our lab began to study effect of Col6 deficiency in the heart by utilizing a global type VI collagen knockout (Col6a1-/-) mouse model. Given the established skeletal muscle phenotype, we predicted that the absence of Col6 would cause deficits in cardiac remodeling following experimentally-induced MI injury. What we found instead was surprising - the knockout of Col6 was cardioprotective: myocyte apoptosis, fibrosis and LV chamber dilation were reduced, and long-term cardiac function was preserved in the Col6 null hearts. The overall goal of this proposal is to determine the critical mechanisms responsible for the post-MI cardioprotection in the absence of Col6. Our hypothesis is that knockout of type VI collagen causes protection from ischemia via preservation of mitochondrial structure and function. The Specific Aims of our proposal are (1) To determine whether knockout of Col6 preserves mitochondrial structure and function to provide protection from MI injury and (2) To silence Col6 with siRNA as a novel therapy to improve post-MI remodeling and cardiac function. These Aims will elucidate the key mechanisms that underlie this cardioprotective effect and test whether silencing Col6 in vivo can provide a therapeutic benefit to treating MI.